The JAK (Janus kinase) family is a tyrosine kinase family consisting of four members, JAK1, JAK2, JAK3 and Tyk (Tyrosine kinase) 2 and plays an important role in cytokine signaling by phosphorylating STATs (signal transducers and activators of transcription).
Analyses of JAK1 knockout mice and JAK1-deficient cells suggest involvement of JAK1 in various receptor-mediated signaling pathways such as IFN (Interferon)α, IFNβ, IFNγ, IL (interleukin)-2, IL-4, IL-6, IL-7 and IL-15 signaling (Non-Patent Document 1). Therefore, regulation of inflammatory responses via these signaling pathways is therapeutically promising for treatment of diseases involving macrophage and lymphocyte activation such as autoimmune diseases and acute and chronic organ transplant rejection.
Analyses of JAK2 knockout mice and JAK2-deficient cells suggest involvement of JAK2 in various receptor-mediated signaling pathways such as EPO (Erythropoietin), TPO (thrombopoietin), IFNγ, IL-3 and GM-CSF (Granulocyte Macrophage colony-stimulating Factor) signaling (Non-Patent Documents 2, 3 and 4). These signaling pathways are supposed to mediate differentiation of erythrocyte or thrombocyte progenitor cells in bone marrow.
Meanwhile, it is suggested that a substitution of phenylalanine-617 with valine in JAK2 is associated with myeloproliferative diseases (Non-Patent Document 2). Therefore, regulation of differentiation of myeloid progenitor cells via these mechanisms is therapeutically promising for treatment of chronic myeloproliferative diseases.
JAK3 plays an important role in various receptor-mediated signaling pathways such as IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 signaling by noncovalently associating with the common γ chain (Non-Patent Documents 5 and 6).
Lowered JAK3 protein levels or defects in the common γ chain gene observed in patients with an immunodeficiency called X-linked Severe Combined Immuno Deficiency (XSCID) suggest that blocking of the JAK3 signaling pathway leads to immunosuppression (Non-Patent Documents 7 and 8).
Animal experiments indicate the importance of JAK3 not only in maturation of B- and T-lymphocytes but also in maintenance of T-lymphocyte functions. Therefore, regulation of immune responses via this mechanism is a promising therapy for T-cell lymphoproliferative diseases such as organ transplant rejection and autoimmune diseases.
In leukemia and lymphoma cells and cells of many solid cancers, JAKs and STATs are activated constitutively (Non-Patent Document 9). This indicates that JAK inhibitors are expected to cure cancer and leukemia by suppressing cancer cell growth.
The JAK inhibitor CP-690, 550 is reported to have improved the pathology of rheumatoid arthritis and psoriasis in clinical tests (Non-Patent Documents 10 and 11) and suppressed rejection in a monkey model of kidney transplantation and airway inflammation in a murine asthma model (Non-Patent Documents 12 and 13).
From these findings, immunosuppression by JAK inhibitors is considered to be useful for prevention or treatment of organ transplant rejection and post-transplant graft-versus-host reaction, autoimmune diseases and allergic diseases. Although compounds having JAK inhibitory action other than CP-690, 550 have been reported (Patent Documents 1 to 15), development of more of such compounds is demanded.
Patent Document 15 reports some tricyclic heterocyclic compounds having JAK inhibitory action, but has no specific description of the compounds of the present invention.